Congestive heart failure (CHF) is a generally progressive, life threatening condition in which myocardial contractility is depressed such that the heart is unable to adequately pump the blood returning to it, also referred to as decompensation. Symptoms include breathlessness, fatigue, weakness, leg swelling, and exercise intolerance. On physical examination, patients with heart failure often have elevated heart and respiratory rates (an indication of fluid in the lungs), edema, jugular venous distension, and enlarged hearts. The most common cause of CHF is atherosclerosis, which causes blockages in the coronary arteries that provide blood flow to the heart muscle. Ultimately, such blockages may cause myocardial infarction with subsequent decline in heart function and resultant heart failure. Other causes of CHF include valvular heart disease, hypertension, viral infections of the heart, alcohol consumption, and diabetes. Some cases of CHF occur without clear etiology and are called idiopathic. The effects of CHF on a subject experiencing the condition can be fatal.
There are several types of CHF. Two types of CHF are identified according to which phase of the cardiac pumping cycle is more affected. Systolic heart failure occurs when the heart's ability to contract decreases. The heart cannot pump with enough force to push a sufficient amount of blood into the circulation leading to a reduced left ventricular ejection fraction. Lung congestion is a typical symptom of systolic heart failure. Diastolic heart failure refers to the heart's inability to relax between contractions and allow enough blood to enter the ventricles. Higher filling pressures are required to maintain cardiac output, but contractility as measured by left ventricular ejection fraction is typically normal. Swelling (edema) in the abdomen and legs is a typical symptom of diastolic heart failure.
CHF is also classified according to its severity. The New York Heart Association classification classifies CHF into four classes:
Class I—no obvious symptoms, with no limitations on physical activity;
Class II—some symptoms during or after normal activity, with mild physical activity limitations;
Class III—symptoms with less than ordinary activity, with moderate to significant physical activity limitations;
Class IV—significant symptoms at rest, with severe to total physical activity limitations.
Typically, a subject progresses through the classes as the subject lives with the condition.
Although CHF is generally thought of as a chronic, progressive condition, it can also develop suddenly. This type of CHF is called acute CHF, and it is a medical emergency. Acute CHF can be caused by acute myocardial injury that affects either myocardial performance, such as myocardial infarction, or valvular/chamber integrity, such as mitral regurgitation or ventricular septal rupture, which leads to an acute rise in left ventricular and diastolic pressure resulting in pulmonary edema, and dyspnea.
Common treatment agents for CHF include, vasodilators (drugs that dilate blood vessels), positive inotropes (drugs that increase the heart's ability to contract), and diuretics (drugs to reduce fluid). Additionally, beta-antagonists (drugs that antagonize beta-adrenergic receptors) have recently become standard agents for treating mild to moderate heart failure. Lowes et al., Clin. Cardiol., 23:III11-6 (2000).
Positive inotropic agents include beta-adrenergic agonists, such as dopamine, dobutamine, dopexamine, and isoproterenol. Dobutamine is commonly given to subjects experiencing late-stage heart failure characterized by severely reduced ventricular ejection fraction or the inability of the subject to undertake physical activity without discomfort. Dobutamine is particularly effective for treating this type of heart failure because of its cardio-selectivity. U.S. Pat. No. 4,562,206 describes dobutamine's cardio-selectivity for the beta-1 adrenergic receptor relative to its activity at the vascular alpha and beta-2 adrenergic receptors. This cardio-selectivity results in a desired positive inotropic effect without a substantial, concomitant increase or decrease in blood pressure. Such blood pressure changes in subjects experiencing heart failure could cause further deterioration in heart function.
However, the use of beta-agonists has potential complications, such as arrhythmogenesis and increased oxygen demand by the heart. Additionally, the initial short-lived improvement of myocardial contractility afforded by these drugs is followed by an accelerated mortality rate resulting largely from a greater frequency of sudden death. Katz, HEART FAILURE: PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott, Williams & Wilkins (1999).
Beta-antagonists antagonize beta-adrenergic receptor function. While initially contra-indicated in heart failure, they have been found to provide a marked reduction in mortality and morbidity in clinical trials. Bouzamondo et al., Fundam. Clin. Pharmacol., 15:95-109 (2001). Accordingly, they have become an established therapy for heart failure. Bouzamondo, supra. However, even subjects that improve under beta-antagonist therapy may subsequently decompensate and require acute treatment with a positive inotropic agent. Unfortunately, as their name suggests, beta-antagonists block the mechanism of action of the positive inotropic beta-agonists that are used in emergency care centers. Bristow et al., J Card. Fail., 7:8-12 (2001).
Additionally, vasodilating agents are also used to treat heart failure. Vasodilators, such as nitroglycerin, have been used for a long period of time to treat heart failure. However, the cause of nitroglycerin's therapeutic effect was not known until late in the last century when it was discovered that the nitric oxide molecule (NO·) was responsible for nitroglycerin's beneficial effects. In fact, the Nobel Prize was awarded in 1998 to three researchers who discovered NO·'s beneficial effects. Opie & White in NITRATES IN DRUGS FOR THE HEART, W. B. Saunder, Philadephia, 33-53 (2001), explain that such compounds are useful for treating heart failure due to their balanced venous and arterial vasorelaxant effects. U.S. Pat. No. 5,212,204 describes a group of NO· donating compounds containing the NONO group. The patent discloses that NO· donated from such compounds has vasodilative properties and can be useful to treat cardiac diseases that would respond favorably to a decrease in blood pressure, including acute congestive heart failure. The patent identifies Angeli's salt (sodium trioxodinitrate or Na2N2O3) as such a compound. Angeli's salt is a compound that can decompose to donate either NO− or NO· depending on the oxidation state of the environment. Fitzhugh & Keefer, Free Radical Biology & Medicine, 28(10):1463-1469 (2000). For example, in the presence of oxidants such as ferricyanide, Angeli's salt decomposes to donate NO·. Fitzhugh & Keefer, supra.
In some subjects experiencing heart failure, a nitric oxide donor is administered in combination with a positive inotropic agent to both cause vasodilation and to increase myocardial contractility. However, this combined administration can impair the effectiveness of positive inotropic treatment agents. For example, Hart et al., Am. J. Physiol. Heart Circ. Pyhsiol., 281:146-54 (2001) reported that administration of the nitric oxide donor sodium nitroprusside, in combination with the positive inotropic, beta-adrenergic agonist dobutamine, impaired the positive intotropic effect of dobutamine. Hare et al., Circulation, 92:2198-203 (1995) also disclosed the inhibitory effect of NO· on the effectiveness of dobutamine.
Researchers have also investigated other forms of nitric oxide to determine their effects on the heart. The nitroxyl species includes the nitroxyl anion (NO−), which is the one-electron reduction product of NO·. Depending on the pH of the environment, the nitroxyl anion may be protenated to HNO. Experiments testing the effects of NO− donors in cardiac diseases have demonstrated that NO− can have a deleterious effect on the myocardium when given to reperfused myocardium. In fact, Ma et al., Proc. Nat'l Acad. Sci., 96(25):14617-14622 (1999) reported that administration of Angeli's salt as an NO− donor to anesthetized rabbits 5 minutes prior to reperfusion (after ischemia) increased myocardial ischemia/reperfusion injury. Also, Takahira et al., Free Radical Biology & Medicine, 31(6):809-815 (2001) reported that administration of Angeli's salt as an NO− donor during ischemia and 5 minutes before reperfusion of rat renal tissue contributed to neutrophil infiltration into the tissue, which is believed to cause ischemia/reperfusion injury.
Patent Cooperation Treaty (PCT) international application PCT/US00/12957 discloses administering a charged nitric oxide species to offset the adverse effects of a potassium channel activator in a method of administering a potassium channel activator to prevent or treat cardiovascular disorders including, among others, congestive heart failure. The only NO− donors described in the application are thionitrates that form disulfide species.